Cancer is the most important disease that causes human death and tremendous financial cost. According to a WHO report in 2004, over 7.4 million lives worldwide were lost to this illness and the victims are still increasing yearly (Abou-Alfa, G. K., et al. (2006), J Clin Oncol 24, 4293-4300. The primary treatments for cancer are surgery, chemotherapy, and radiotherapy. However, these traditional therapies cause serious side effects and kill normal cells as well.
For this reason, targeted therapies were developed and proved to be effective in treating several types of cancer effectively (Van Cutsem, E., et al. (2009), N Engl J Med 360, 1408-1417, Klein, S. and Levitzki A. (2007), Adv Cancer Res 97, 295-319). However, there are few tumor specific markers and only few targeted therapies were successfully applied in the clinic (Jain, R. K., et al. (2009), Nat Rev Clin Oncol 6, 327-3384, Gazdar, A. F. (2009), Oncogene 28 Suppl 1, S24-31). Moreover, many studies have shown that the genomic instability facilitates resistance to targeted therapies (Dassie, J. P., et al. (2009), Nat Biotechnol 27, 839-849, Sica, A., Schioppa, T., Mantovani, A., and Allavena, P. (2006), Eur J Cancer 42, 717-727). More recently, reports have indicated that the surrounding tumor microenvironment is strongly associated with tumor progression, particularly immune evasion (Pollard, J. W. (2004), Nat Rev Cancer 4, 71-78, de Visser, K. E., and Coussens, L. M. (2006), Contrib Microbiol 13, 118-137, Stewart, T. J., and Abrams, S. I. (2008), Oncogene 27, 5894-5903, Joyce, J. A., and Pollard, J. W. (2009), Nat Rev Cancer 9, 239-252).
Several cell types have been suggested to play key roles in the tumor microenvironment and are involved in tumor progression, including tumor-associated macrophages (TAM), regulatory T cells (Treg), natural killer (NK) cells and CD8+ T-cells (Solinas, G., Germano, G., Mantovani, A., and Allavena, P. (2009), J Leukoc Biol 86, 1065-1073, Zou, W. (2006), Nat Rev Immunol 6, 295-307, Whiteside, T. L. (2006), Cancer Treat Res 130, 103-124, Coffelt, S. B., Hughes, R., and Lewis, C. E. (2009), Biochim Biophys Acta 1796, 11-18). NK and CD8+ T-cells are two major effective cell types to eradicate abnormal tumor cells by cell-mediated cytotoxicity. Treg cells represent a small fraction (5-6%) of the overall CD4+ T cells (Wang, R. F., Peng, G., and Wang, H. Y. (2006), Semin Immunol 18, 136-142) and is another major regulatory cell type in tumor microenvironment. Under normal circumstances, Treg cells protect the host from self-reactive T-cells and, therefore, prevent the formation of autoimmune disease (Corthay, A. (2009), Scand J Immunol 70, 326-336). However, in tumor microenvironment, Treg can secrete cytokines, such as IL-10 and TGF-β, to inhibit the function of tumor-targeted innate (NK cells) and adaptive (CD8+ T-cells) immune response (Bingle, L., Brown, N. J., and Lewis, C. E. (2002), J Pathol 196, 254-265) and protect tumor cells from immune clearance (Andrew, G. et al. (2006), J Immunol 177, 896-904).
One protein receptor that can down-regulate the immune system in the tumor microenvironment is Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), also known as cluster of differentiation 152 (CD152). CTLA-4 is found on the surface of T cells, which lead the cellular immune attack on antigens. While the T cell attack can be turned on by stimulating the CD28 receptor on T cells, it can be turned off by stimulating the CTLA4 receptor.
While antibodies are commonly used to target disease proteins, they have their limitations, including high production costs, low stability, and are restricted in many cases as to the epitopes they can target. Aptamers have several advantages that make it suitable for therapeutic application such as lower molecular weight that allows easier penetration through tissues, low cost in chemical synthesis, established modification methods and high stability. It is therefore of great interest to develop suitable aptamers having high affinity to a target protein.